title: Ubiquitous hazardous metal lead induces TNF-α in human phagocytic THP-1 cells: primary role of ERK 1/2.
abstract: Induction of tumor necrosis factor-α (TNF-α) in response to lead (Pb) exposure has been implicated in its immunotoxicity. However, the molecular mechanism by which Pb upregulates the level of TNF-α is wagely known. An attempt was therefore made to elucidate the mechanistic aspect of TNF-α induction, mainly focusing transcriptional and post transcriptional regulation via mitogen activated protein kinases (MAPKs) activation. We observed that exposure of Pb to human monocytic THP-1 cells resulted in significant enhanced production of TNF-α m-RNA and protein secretion. Moreover, the stability of TNF-α m-RNA was also increased as indicated by its half life. Notably, activation of ERK 1/2, p38 and JNK in Pb exposed THP-1 was also evident. Specific inhibitor of ERK1/2, PD 98059 caused significant inhibition in production and stability of TNF-α m-RNA. However, SB 203580 partially inhibited production and stability of TNF-α m-RNA. Interestingly, a combined exposure of these two inhibitors completely blocked modulation of TNF-α m-RNA. Data tends to suggest that expression and stability of TNF-α induction due to Pb exposure is mainly regulated through ERK. Briefly, these observations are useful in understanding some mechanistic aspects of proinflammatory and immunotoxicity of Pb, a globally acknowledged key environmental contaminant.
authors.affiliation: Fiber Toxicology Division, Indian Institute of Toxicology Research, Council of Scientific & Industrial Research, Mahatma Gandhi Marg, PO Box 80, Lucknow 226001, UP, India.
authors.forename: Mohd Imran
authors.initials: MI
authors.lastname: Khan
authors.forename: Najmul
authors.initials: N
authors.lastname: Islam
authors.forename: Amogh A
authors.initials: AA
authors.lastname: Sahasrabuddhe
authors.forename: Abbas Ali
authors.initials: AA
authors.lastname: Mahdi
authors.forename: Huma
authors.initials: H
authors.lastname: Siddiqui
authors.forename: Mohd
authors.initials: M
authors.lastname: Ashquin
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ahmad
mesh_terms: D002460:Cell Line; D015386:Hazardous Substances / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007854:Lead / Q000276:immunology / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D015386:Hazardous Substances; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007854:Lead; D048052:Mitogen-Activated Protein Kinase 3